The molecular basis for peptide repertoire selection in the human leukocyte antigen (HLA) C*06:02 molecule

Mobbs, Jesse I., Illing, Patricia T., Dudek, Nadine L., Brooks, Andrew G., Baker, Daniel G., Purcell, Anthony W., Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 and Vivian, Julian P. 2017. The molecular basis for peptide repertoire selection in the human leukocyte antigen (HLA) C*06:02 molecule. Journal of Biological Chemistry 292 (42) , pp. 17203-17215. 10.1074/jbc.M117.806976

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Abstract

Human leukocyte antigen (HLA)-C*06:02 is identified as the allele associated with the highest risk for the development of the autoimmune skin disease psoriasis. However, the diversity and mode of peptide presentation by the HLA-C*06:02 molecule remains unclear. Here, we describe the endogenous peptide repertoire of ∼3,000 sequences for HLA-C*06:02 that defines the peptide-binding motif for this HLA allomorph. We found that HLA-C*06:02 predominantly presents nonamer peptides with dominant arginine anchors at the P2 and P7 positions and a preference for small hydrophobic residues at the C terminus (PΩ). To determine the structural basis of this selectivity, we determined crystal structures of HLA-C*06:02 in complex with two self-peptides (ARTELYRSL and ARFNDLRFV) and an analogue of a melanocyte autoantigen (ADAMTSL5, VRSRR-abu-LRL) implicated in psoriasis. These structures revealed that HLA-C*06:02 possesses a deep peptide-binding groove comprising two electronegative B- and E-pockets that coincide with the preference for P2 and P7 arginine anchors. The ADAMTSL5 autoantigen possessed a P7-Leu instead of the P7-Arg residue, but nevertheless was accommodated within the HLA-C*06:02 antigen-binding cleft. Collectively, our results provide the structural basis for understanding peptide repertoire selection in HLA-C*06:02.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	American Society for Biochemistry and Molecular Biology
ISSN:	0021-9258
Date of First Compliant Deposit:	30 July 2018
Date of Acceptance:	30 August 2017
Last Modified:	20 Nov 2024 01:45
URI:	https://orca.cardiff.ac.uk/id/eprint/110477

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